The invention relates to new derivatives of 2-propylpentanoic acid (valproic acid, hereinafter VPA), and 2-propyl-2-pentenoic acid, their preparation and use as antiepileptic agents.
VPA and its alkali salts are major drugs in the arsenal of drugs for the treatment of epileptic seizures and convulsions. However, approximately 25% of epileptic patients do not respond to current treatment. Furthermore, VPA itself has considerable adverse effects including hepatotoxicity and teratogenicity. Baille, T. A. and A. W. Rettenmeier, in "Antiepileptic Drugs," ed. by R. H. Levy, F. E. Dreifuss, R. H. Mattson, B. S. Meldrum and J. K. Penry, Raven Press, New York (1989), at 601-619.
One approach to obtain improved antiepileptic agents has been to prepare the primary amide derivatives of VPA and its analogs. M. Bialer, Clin. Pharmacokinet. 20:114-122 (1991); M. Bialer, A. Haj-Yehia, N. Barzaghi, F. Pisani, and E. Perucca, Eur. J. Clin. Pharmacol., 289-291 (1990); A. Haj-Yehia and M. Bialer, J. Pharm. Sci., 79: 719-724 (1990). While certain glycinamide derivatives have been disclosed by R. Roncucci, et al., U.S. Pat. No. 4,639,468, issued Jan. 27, 1987, these compounds generally have not been accepted into clinical practice. Thus, an urgent need still exists in the art for developing anti-convulsant agents with improved efficacy and a wider margin between the dose which is therapeutic and that which is neurotoxic.
VPA and 2-ene-VPA-related glycine amides have been disclosed by Granneman, et al., Xenobiotica, 14, 375 (1984), to be minor metabolites of VPA. However, an examination of the mass spectral data therein shows that those compounds are in fact VPA and 2-ene-VPA glycine and cannot be glycinamide conjugates, wherein the glycine nitrogen moiety is attached to the VPA or 2-ene-VPA carbonyl. While Granneman, et al., described these compounds as glycine conjugates, they erroneously named them as VPA and 2-ene-VPA glycinamides, rather than valproyl and 2-ene-valproyl glycine; the latter names are in accord with the method of preparation and the mass spectral data reported by Granneman, et al.